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    • br Materials and methods br Results Estimations

    2022-07-12


    Materials and methods
    Results Estimations of OMP generated by the proposed mechanism (Fig. 1) were first performed for the range of 0.001–2 mM of protein kinase g concentration in the cytosol. It was assumed that only 5% of all VDACs in MOM form the ANT-VDAC1-HKI contact sites, and that the fraction of the VDAC3 isoform represents 10% of all VDACs in MOM, i.e. NV3 = 0.10 (in Eq. (1)). The VDAC3 isoform was considered a permanently open channel. The system of Eqs. (1), (2), (4), (5), (6), (7), (8) was solved for mitochondria at Δψi = −140 mV, [ATP]m/[ADP]m = 3, 0.15 mM glucose-6-phosphate in the cytosol (Eq. (6)) and VDAC voltage-gating properties described by Eq. (2) (Fig. 3A, C, E) or Eq. (3) (Fig. 3B, D, F), with Pc = 0.2 (Fig. 3A–D) or Pc = 0.1 (Fig. 3E, F). The model showed significantly different dependencies of the calculated OMP on the glucose concentration in the cytosol (Fig. 3, curves a) for the cases of VDAC voltage-gating properties described by Eq. (2) (Fig. 3A, C) and Eq. (3) (Fig. 3B, D), both at Pc = 0.2. For the case described by Eq. (3), at 10% fraction of VDAC3 (NV3 = 0.10) in MOM (Fig. 3B), there were observed a sharp increase in calculated OMP (Fig. 3B, a) and a sharp OMP-dependent restriction of the MOM permeability to Pi− (Fig. 3B, b) at the threshold concentrations of glucose. Relatively smooth changes were demonstrated for the case described by Eq. (2) (Fig. 3A, a and b, respectively). On the other hand, the magnitudes of calculated positive OMP for both cases were high enough (Fig. 3A, a and B, a, respectively) to completely close the fraction Nv of voltage-sensitive VDACs in MOM, at glucose concentrations higher than 1.3 mM (Fig. 3A, b), or higher than 0.4 mM (Fig. 3B, b). Lower values of OMP were calculated assuming a higher content of the VDAC3 fraction (NV3 = 0.15) in MOM (Fig. 3C, D, curves a), showing monotonic increase in generated OMP with an increase in the glucose concentration for the case of the VDAC voltage-gating properties described by Eq. (2) (Fig. 3C, a). Nonetheless, for the case described by Eq. (3), a sharp increase in generated OMP was still observed at threshold levels of glucose (Fig. 3D, a). As a result, only for the last case, the model showed a sharp OMP-dependent decrease in MOM permeability to Pi− (Fig. 3D, b) in comparison to relatively monotonic changes obtained for the case described by Eq. (2) (Fig. 3C, b). Assuming a more profound electrical closure of VDACs for Pi− permeability, i.e. Pc = 0.1 in Eqs. (2), (3), the model demonstrated significantly higher sharpness in the glucose-dependent increase of calculated OMP even at NV3 = 0.15, for both cases described by Eq. (2) (Fig. 3E, a) and Eq. (3) (Fig. 3F, a). The mentioned increased sharpness in the glucose-dependent increase of OMP at Pc = 0.1 and the voltage sensitivity parameter S = 30 V−1 also resulted in a very sharp decrease in the MOM permeability to Pi− (Fig. 3E, b and F, b, respectively). No glucose-dependent restriction of MOM permeability to Pi− was obtained assuming zero voltage sensitivity of VDAC's, S = 0 V−1, for all the cases considered above (curves c in Fig. 3A–F). The proposed model also demonstrated an almost hyperbolic increase in the steady-state metabolic flux Ics through the ANT-VDAC1-HKI contact sites with an increase in the glucose concentration (curves d in Fig. 3A–F). Interestingly, only slight OMP-dependent restrictions of Ics were shown even at the highest values of calculated OMP (curves d in Fig. 3A–F) in comparison to the case of zero voltage sensitivity of free VDAC's in MOM, i.e. at S = 0 V−1 (curves e in Fig. 3A–F). The next analysis of the model was performed varying the percentage of VDACs forming ANT-VDAC1-HKI contact sites (AVH, % in Fig. 4) from 2% to 6% of all VDACs in MOM (Ncs = 0.02–0.06). The system of Eqs. (1), (2), (4), (5), (6), (7), (8) was solved for the range of glucose concentrations of 0.001–1 mM at Δψi = −140 mV, Pc = 0.2, S = 30 V−1 and the VDAC3 fraction in MOM NV3 = 0.15 (15%) (Fig. 4A, D, G). The calculated positive OMP was relatively low at 2–4% of VDACs forming ANT-VDAC1-HKI contact sites, and significantly increased at a percentage greater than 5% (Fig. 4A).